Developmental origins of fusion-negative rhabdomyosarcomas

Abstract

Rhabdomyosarcomas (RMS) are very heterogeneous tumors that can be divided into three major groups: alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma, and pleomorphic rhabdomyosarcoma. Concerted efforts over the past a decade have led to an understanding of the genetic underpinnings of many human tumors through genetically engineered models; however, left largely behind in this effort have been rare tumors with poorly understood chromosomal abnormalities including the vast majority of RMS lacking a pathognomonic translocation, i.e. fusion-negative RMS. In this chapter, we review the characteristic genetic abnormalities associated with human RMS and the genetically engineered animal models for these fusion-negative RMS. We explore not only how specific combinations of mutations and cell of origin give rise to different histologically and biologically distinguishable pediatric and adult RMS subtypes, but we also examine how tumor cell phenotype (and tumor "stem" cell phenotype) can vary markedly from the cell of origin.

Figure 2.1

Model of skeletal myogenesis and possible cellular origins of fusion-negative RMS. Prenatal muscle development and postnatal muscle maintenance and regeneration are regulated by Pax3, Pax7, and muscle regulatory factors (MyoD, Myf5, Myogenin, and Myf6). Cell of origin for pleomorphic RMS might be an adult satellite cell. Meanwhile, cell of origins for ERMS might be a differentiating late myoblast.